Project Summary: Changes in glutamate neurotransmission in the transition to aversion-resistant alcohol drinking (CTG) Alcohol use disorders (AUDs) are among the most pervasive and costly health issues in the United States and decades of research has provided strong evidence that genetics, and in particular a family history of alcoholism, plays a pivotal role in the development of AUDs. Alcoholism is a chronic, relapsing, and progressive disorder and a key feature in the transition to alcohol dependence is the development of aversion resistant (ARD) drinking accompanied by a decrease in control of alcohol drinking. The medial prefrontal cortex (MPF) is a center for decision making and receives input from multiple cortical and limbic brain regions. Two sub-regions of the MPF thought to play different roles in the transition to alcohol dependence are the prelimbic (PL) and infralimbic (IL) cortices with activation of PL circuits increasing drug seeking whereas activity in the IL decreases drug seeking after extinction. Current theories of addiction suggest that the transition to compulsive drinking is associated with the emergence of hyper-glutamatergic activity in brain regions receiving significant glutamatergic input from the PL cortex. A common model used to study ARD in rodents is quinine-resistant drinking, where, after a history of ethanol drinking, rodents show a willingness to drink quinine-adulterated ethanol solutions. The alcohol-preferring (P) rat is an excellent resource to model family history of alcoholism in rats, however, no studies have used this resource to investigate the mechanisms underlying quinine-resistant drinking. This represents a critical gap in the literature which we will begin to address in this application. The long-term goal of this project is to identify neurobiological changes associated with the transition to ARD in a suitable model of AUDs. The objective of this component is to determine the role of glutamate transmission within sub-regions of the MPF in the transition to quinine-resistant alcohol drinking using the P-rat as a genetic model of AUDs. The rationale for this work is that by understanding glutamatergic function in all parts of the reward system we can begin to identify mechanisms that underlie the transition to compulsive drinking. The Central Hypothesis states: the transition to quinine-resistant drinking involves increases in the activity of glutamate systems within the PL cortex, but not the IL cortex. AIM 1 studies how alcohol drinking leading to quinine-resistance drinking by P-rats alters glutamate transmission in the IL and PL cortices, as measured by quantitative microdialysis. AIM 2 examines how the development of quinine-resistance drinking changes the in vivo release of glutamate within the PL and IL cortices during alcohol drinking episodes. AIM 3 will examine the effects of local microinjection of ionotropic glutamate receptor antagonists into the PL and IL cortices on ethanol drinking in quinine-resistant vs. quinine-sensitive P-rats. Overall, the results of this component will help lay the foundation for developing pharmacotherapies for treating AUDs. These results will be bi-directionally informative with the other ARC components and as a group will combine to significantly advance the field.